US9878982B2 - Pyridine derivatives and anti-mycobacterial use thereof - Google Patents

Pyridine derivatives and anti-mycobacterial use thereof Download PDF

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US9878982B2
US9878982B2 US15/325,824 US201515325824A US9878982B2 US 9878982 B2 US9878982 B2 US 9878982B2 US 201515325824 A US201515325824 A US 201515325824A US 9878982 B2 US9878982 B2 US 9878982B2
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dimethylamino
phenylbutan
naphthalen
methoxy
compound
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US20170174628A1 (en
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Zhaozhong DING
Shuhui Chen
Zhigang Huang
Wei Luo
Zhe CAI
Yepeng WANG
Dongdong TANG
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CISEN PHARMACEUTICAL Co Ltd
Shanghai Jia Tan Pharmatech Co Ltd
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/06—Antibacterial agents for tuberculosis
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/647—One oxygen atom attached in position 2 or 6 and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • the present invention relates to a preparation method and use of a series of novel pyridine derivatives.
  • Such derivatives are useful for treating mycobacterium related diseases, especially for treating diseases caused by pathogenic mycobacteria, such as M. tuberculosis, M. bovis, M. avium , and M. marinum.
  • Mycobacterium tuberculosis is the pathogen of tuberculosis. As a globally widespread and a fatal infectious disease, about more than 8 million people were infected annually and 2 million people died from tuberculosis, according to the World Health Organization. In the last decade, tuberculosis cases have increased at a rate of 20% worldwide, particularly in poor areas. If this trend continues, tuberculosis cases are very likely to continue to increase at a rate of 41% over the next two decades. In the first 50 years after the initial application of chemotherapy, tuberculosis had always been the main infectious disease leading to adult death, only second to AIDS.
  • tuberculosis The complications of tuberculosis led to the emergence of many resistant strains, which also developed a symbiotic relationship with AIDS.
  • the population infected with tuberculosis whose HIV tests were positive is 30 times more likely to develop into active tuberculosis compared to the population whose HIV tests were negative. On average, one out of every three people who died of AIDS was caused by tuberculosis.
  • a formula recommended by the U.S. Public Health Service includes a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by a combination of isoniazid and rifampicin for four months.
  • a formula recommended by the U.S. Public Health Service includes a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by a combination of isoniazid and rifampicin for four months.
  • use of this drug combination needs to be extended to seven months.
  • the drug combination needs contain additional drugs, such as ethambutol tablets, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin.
  • additional drugs such as ethambutol tablets, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin.
  • Multidrug-resistant tuberculosis is mainly resistant to isoniazid and rifampicin in the four standard therapy drugs. Multidrug-resistant tuberculosis can be fatal if leaving untreated or if the standard therapy for the common tuberculosis is used. Therefore, the treatment of such disease requires the use of second-line drugs to two years. Most of these second-line drugs are toxic, expensive, and of low efficacy. Due to the absence of effective treatment, patients with contagious drug-resistant tuberculosis continue to spread the disease. Therefore, for multidrug-resistant tuberculosis, a new drug having a new action mechanism is highly desired.
  • WO2004/01436 described a compound which is effective for treating tuberculosis, in particular for tuberculosis infected with multidrug-resistant Mycobacterium tuberculosis .
  • the compound has the formula (Ia):
  • TMC207 a novel anti-tuberculosis weapon
  • TMC207 (also known as R207910, or Compound ‘J’) is a diarylquinoline. The compound inhibits the proton pump of M. tuberculosis ATP synthase. TMC207 was obtained by Johnson & Johnson through screening more than 70,000 compounds against the saprophytic Mycobacterium smegmatis which grows more rapidly and controllably than M. tuberculosis does. TMC207 (Sirturo) is the first anti-tuberculosis and energy-metabolism-interfering drug that applied a new mechanism of action. The US Food and Drug Safety Agency and the European Commission approved Sirturo as part of a combination therapy for adult multidrug-resistant tuberculosis in late 2012 and March 2014, respectively.
  • the present invention aimed at developing a new type of pyridine derivatives which can inhibit the growth of mycobacterium, thereby achieving the effective treatment of the diseases caused by M. tuberculosis, M. bovis, M. avium , and M. marinum.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, prodrug, stereoisomer or tautomer thereof,
  • R 1 is selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, C( ⁇ O)NH 2 , S( ⁇ O)NH 2 , S( ⁇ O) 2 NH 2 , or the following group optionally substituted with 0, 1, 2 or 3 R 01 : C 1-10 hydrocarbyl, C 1-10 heterohydrocarbyl, C 3-10 cyclohydrocarbyl, C 3-10 heterocyclohydrocarbyl, C 1-10 hydrocarbyl substituted with C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl, C 1-10 heterohydrocarbyl substituted with C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl; m is 0, 1, 2 or 3; R 2 is selected from H, halogen, haloalkyl, OH, CN, NH 2 , or the following group optionally substituted with 0, 1, 2 or 3 R 01 : C 1-10 hydrocar
  • R 1 is selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, C( ⁇ O)NH 2 , S( ⁇ O)NH 2 , S( ⁇ O) 2 NH 2 , R 11 or
  • R 11 is selected from the following group optionally substituted with 0, 1, 2 or 3 R 01 : C 1-6 alkyl, C 1-6 heteroalkyl, N,N-di(C 1-6 alkyl)amino-(CH 2 ) 0-3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered cyclohydrocarbyl and 5-6 heterocyclohydrocarbyl.
  • R 1 is selected from H, F, Cl, Br, I, R 101 and
  • R 101 is selected from the following group optionally substituted with 1, 2 or 3 F, Cl, Br, I, CH 3 , CF 3 , CH 3 O or CF 3 O: phenyl, pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, C 1-6 alkyl, N,N-di(C 1-6 alkyl)amino-(CH 2 ) 0-3 , C 3-4 cycloalkyl,
  • D 101 is selected from CH 2 , O, S, NH and N(CH 3 ); D 102 is CH 2 or a single bond; and T 101 is CH or N.
  • R 1 is selected from:
  • R 2 is selected from H, halogen, hydroxyl, or the following group optionally substituted with 0, 1, 2 or 3 R 01 : C 1-6 alkyl or C 1-6 alkoxy.
  • R 2 is selected from H, halogen, hydroxyl, CH 3 O and CF 3 .
  • R 3 is selected from the following group optionally substituted with 0, 1, 2 or 3 R 01 : phenyl-(CH 2 ) 0-3 , naphthyl-(CH 2 ) 0-3 and C 3-6 cycloalkyl-(CH 2 ) 0-3 .
  • R 3 is selected from:
  • R 4 , R 5 and R 6 are each independently selected from C 1-6 alkyl optionally substituted with 0, 1, 2 or 3 F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, C( ⁇ O)NH 2 , S( ⁇ O)NH 2 or S( ⁇ O) 2 NH 2 .
  • R 4 , R 5 and R 6 are each independently selected from CH 3 and
  • the above compound is selected from:
  • the present invention also provides a method for preparing the above compounds, which is selected from:
  • the present invention further provides use of the above compounds in the manufacture of a medicament for the treatment of a M. tuberculosis disease.
  • the compounds of the present invention Upon tested, the compounds of the present invention have shown a significant therapeutical efficacy on mycobacterial diseases, especially on the diseases caused by M. tuberculosis, M. bovis, M. avium , and M. marinum . Therefore, as a drug, in addition to the compounds of formula (I) defined above, the present invention also encompasses pharmaceutically acceptable acid addition salts or base addition salts, stereochemically isomeric forms, and tautomeric forms.
  • the present invention also comprises a pharmaceutically acceptable carrier, and effective components to achieve a therapeutic purpose.
  • the compounds of the present invention may be made into different formulations. All applicable pharmaceutical ingredients may be used by systematic drug by reference.
  • the preparation of the pharmaceutical ingredients of the present invention combines an effective dose of a particular compound (or salt form) as an active ingredient, and a pharmaceutically acceptable carrier which has a wide range of use forms according to examples of drug administration.
  • the pharmaceutical ingredients are administered in the same dosage form, in particular orally or by injection.
  • any usual pharmaceutical media may be used, such as water, glycerol, oil, alcohol, and the like to prepare an oral formulation (e.g., suspension, syrup, elixir, emulsion, solution); or starch, sugar, kaolin, diluent, lubricant, binder, disintegrating agent to prepare a solid carrier (e.g., powder, pill, capsule, and tablet).
  • a solid carrier e.g., powder, pill, capsule, and tablet.
  • tablets and capsules are the most advantageous pharmaceutical carrier.
  • pure water accounts for the largest proportion of the carrier, and other materials are also included, for example, a medium to increase the solubility.
  • the preparation of an injectable solution typically contains a physiological saline, glucose solution, or a combination thereof.
  • the preparation of an injectable suspended solution contains a suitable liquid carrier, such as a suspension auxiliary agent and the like.
  • a solid form prepared is usually converted into a liquid form immediately after use.
  • the active ingredient should account for 0.05% to 99%, more preferably 0.1 to 70%, more preferably, 1 to 99.95%, yet more preferably 30 to 99.9%, of the total weight of the drug carrier.
  • Medicaments also may contain a number of added ingredients, such as lubricant, stabilizer, buffer, emulsifier, viscosity modifier, surfactant, preservative, flavoring or coloring agent.
  • lubricant such as lubricant, stabilizer, buffer, emulsifier, viscosity modifier, surfactant, preservative, flavoring or coloring agent.
  • the above additives will be kept in the same dosage form, but with different amounts.
  • “The same dosage form” herein means a physically discrete unit relative to the dose, wherein each unit contains an effective dose calculated in advance to achieve a therapeutic purpose as well as the required drug carrier. Examples of such same dosage form include (scored, coated) tablet, capsule, pill, powder packet, wafer, anal suppository, injectable solution or injectable suspension, and other similar forms, or any combination thereof.
  • the daily dose of the compound of the present invention should be adjusted according to the different compound, administration scheme, desired effect, and disease conditions. However, in general, in order to achieve satisfactory therapeutic results, the daily dose is recommended not to exceed 1 gram, such as 10 to 50 mg of per kilogram of body weight.
  • the present invention relates to use of the compounds of formula (I), pharmaceutically acceptable acid addition salts or base addition salts, stereochemically isomeric forms, tautomeric forms, as well as any medicament for treating mycobacterial diseases manufactured industrially through use of the above pharmaceutical ingredients.
  • the present invention provides a method for treating a patient afflicted or infected with mycobacterial diseases, which method comprises administering an effective dose or pharmaceutical components to the patient.
  • C 1-10 is selected from the group consisting of C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 ; and C 3-10 is selected from the group consisting of C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 .
  • C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalky, C 1-10 oxa-alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl are included, but not limited to: C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl) amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkyloxyacyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkanoyl, C 3-10 cycloalkyloxy
  • N(CH 3 ) 2 NH(CH 3 ), —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 F, —CH 2 CH 2 S( ⁇ O) 2 CH 3 , —CH 2 CH 2 CN,
  • pharmaceutically acceptable means that the referenced compounds, materials, compositions, and/or dosage forms are, within the scope of reliable medical judgment, suitable for access by human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention which are prepared from the compounds having particular substituent moieties found in the present invention and relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting a sufficient amount of base with the neutral form of such compounds in a neat solution or in a suitable inert solvent.
  • the pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting a sufficient amount of acid with the neutral form of such compounds in a neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, phosphorous acids and the like; as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic acid and the like (see, Berge et al, “Pharmaceutical salts”, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the parent compounds are easily prepared by the reaction of the salt with a base or acid and then isolation.
  • the prototype of a compound differs from its various salt forms in physical properties (such as the solubility in a polar solvent).
  • pharmaceutically acceptable salt refers to derivatives of the compounds disclosed, while the prototype of the compound is derived from the transformation of an acid or basic salt.
  • the pharmaceutically acceptable salt includes, but is not limited to—an organic acid salt of mineral, or a basic residue (e.g., amines); an organic base salt of alkali metal or acidic residue (e.g., carboxylic acid).
  • Pharmaceutically acceptable salts include common non-toxic salt or a quaternary ammonium salt derived from a prototype compound (eg, non-toxic inorganic/organic acid).
  • Common non-toxic salts include, but are not limited to—a salt derived from inorganic or organic acid, e.g., carbethoxybenzoic, isethionic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycolic p-arsanilic acid, hexylisophthalic, hydrabaminic, hydrobromic, hydrochloric, hydroiodic, hydroxylmaleic, hydroxylnaphthoic, hydroxylsulfonic, lactic, lactose, dodecyl sulfonic, maleic, malic, mandelic, methanesulfonic, naphthalene sulfonic, nitric, oxalic, Pamoic, pan
  • the pharmaceutically acceptable salts can be prepared from the parent compounds containing acid radical or base radical.
  • such salts can be prepared by the reaction of a free acid or base with another suitable base or acid in water or in an organic solvent (non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) or a mixture of both.
  • the compounds provided by the present invention have prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may be presented in non-solvated form or solvated form including hydrate form.
  • the non-solvated form is equivalent to the solvated form, and both forms are within the scope of the present invention.
  • Certain compounds of the present invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemate, diastereomer, geometric isomer and individual isomer are included within the scope of the present invention.
  • the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985). Unless otherwise stated, solid and broken wedges are used to denote the absolute configuration of a chiral element. Unless otherwise stated, when the compounds in the present invention contain olefinic double bond and other geometric asymmetry centers, they contain E, and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.
  • the compounds of the present invention may have particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, ( ⁇ )- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, for example, enantiomers or diastereoisomers enriched mixtures, all of which belong to the scope of the present invention.
  • the substituents such as alkyl, etc. may have additional asymmetric carbon atoms. All these isomers and mixtures thereof are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers, or (D)- and (L)-isomers may be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one kind of enantiomer of certain compound of the present invention is to be obtained, the pure desired enantiomer can be obtained by asymmetric synthesis or derivative action of chiral auxiliary followed by separating the resulting diastereomeric mixture and cleaving the auxiliary group.
  • the compound when the molecule contains a basic functional group (such as amino) or acidic functional group (such as a carboxyl), the compound reacts with an appropriate optically active acid or base to form a salt of diastereomeric isomer, then the diastereomeric isomer is subjected to resolution through fractional crystallization or chromatography well known in the art and recover to give pure enantiomer.
  • the enantiomers and diastereoisomers are generally separated through chromatography which uses a chiral stationary phase and optionally a chemical derivative method (for example, carbamate generated by amine).
  • the compound of formula I is a particular mixture of enantiomers (hereinafter referred to as diastereoisomer A or B), thereby distinguished from other diastereomers. Since the compound of formula I has two chiral centers, the compound is determined to be a mixture, particularly a racemic mixture of (R, S) and (S, R) enantiomers, or of (R, R) and (S, S) enantiomers. In the description below, the two enantiomers in the mixture are called diastereoisomer A or B. Whether the racemic mixture is defined as A or B depends on which one (A or B) is firstly separated in the synthesis step.
  • the compound of formula I is a particular enantiomer (different from other enantiomers). Since the compound of formula I has two chiral centers, the compound is determined to be (R, S), (S, R), (R, R) or (S, S) enantiomer which corresponds to A1, A2, B1 or B2 described hereinafter respectively. Whether the enantiomer is defined as A1, A2, B1 or B2 depends on whether such enantiomer is separated firstly or secondly from the synthesis step and whether isolated from diastereomer A or B.
  • R or S symbol when there are two stereocenters in the known absolute configuration in a molecule, R or S symbol should be marked on the chiral center having the lowest numbering, namely reference center (according to Cahn-Ingold-Prelog Rule).
  • the [R*, R*] or [R*, S*] mark indicates the configuration of the second stereocenter, R* commonly referred to as the reference center.
  • [R*, R*] represents that the compound has identical chiral centers
  • [R*, S*] represents that the compound has different chiral centers. For example, if the lowest-numbered chiral center in the molecule has S configuration and the second chiral center has R configuration, the corresponding symbol is S-[S*, S*].
  • the highest priority substituent position When “ ⁇ ” and “ ⁇ ” signa are also used, on the asymmetric carbon atom in the ring with the minimum numbered element, the highest priority substituent position always be marked as “a” position of plane in the ring system. Relative to the highest priority substituent position on the reference carbon atom, the highest priority substituent position on another asymmetric carbon atom on the same side of the plane is marked as “ ⁇ ”, and that of the other side of the plane is marked as “ ⁇ ”.
  • the compound of formula I and some intermediate compounds always have at least two stereocenters to derive at least four different structures.
  • Compound of formula I can be synthesized in a form of an enantiomeric mixture (in particular a racemic mixture), and also may be isolated according to conventional procedures.
  • the reaction of the racemic compound of formula I with a chiral acid may convert the compound into the corresponding diastereomeric salt.
  • the diastereomeric salt can be isolated in a subsequent step, e.g., by selective crystallization or fractional crystallization, and the enantiomer may be separated with an alkali metal.
  • Another method for separating the diastereomeric salt of the compound of formula I is liquid phase separation using a chiral stationary phase.
  • the compound can be prepared by specific stereo methods. The advantage of such method is to introduce the stereo conformation from pure raw materials.
  • the tautomeric form of the compound of formula I is also included in the compounds having formula (I).
  • an enol is converted to a ketone (ketone-enol tautomerism).
  • the tautomers of the compounds of formula I or of the intermediate compounds disclosed herein are also within the protection scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • pharmaceutically acceptable carrier refers to any agent or carrier medium which is capable of delivering an effective amount of the active substances of the present invention, does not interfere with the biological activity of the active substances and has no toxic side effects on the host or patient.
  • the representative carrier includes water, oil, vegetable and mineral, cream base, lotion base, ointment base and the like. These bases include suspending agents, thickeners, penetration enhancers and the like. Their formulations are well known to the skilled in the cosmetic field or topical pharmaceutical field. The additional informations about the carrier can be referred to Remington: The Science and Practice of Pharmacy, 21st Ed, Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or vehicle required for formulating an effective pharmaceutical composition.
  • an “effective amount” or “therapeutically effective amount” refers to a nontoxic but sufficient amount to achieve the desired effect of the drug or agent.
  • an “effective amount” of an active substance in the composition refers to an amount required for achieving the desired effect when combining with another active substance in the composition.
  • An effective amount varies from person to person and is determined depending on the age and general condition of the recipient as well as the specific active substance. The appropriate effective amount in an individual case can be determined by the skilled in the art based on routine experiment.
  • active ingredient refers to a chemical entity which can effectively treat the target disorder, disease or condition.
  • “Substituted” as used herein means one or more hydrogen atoms on an atom are substituted with a particular group, such case including deuterium (D) atom, an isotope of hydrogen atom, such that the valence of the original atom does not overflow, thus rendering the compound more stable.
  • the substituent group is a ketone (eg, ⁇ O)
  • the two hydrogen atoms are substituted.
  • Positions on an aromatic ring can not be substituted with a ketone.
  • the term “optionally substituted” means, unless otherwise specified, the type and number of the substituents are not limited as long as it can be achieved in chemistry whether an atom can be replaced by a substituent or not.
  • one of the variables When one of the variables is selected from a single bond, it represents that the two groups linked by the single bond are connected directly. For example, when L in A-L-Z represents a single bond, the structure of A-L-Z is actually A-Z.
  • alkyl substituents are generally known as “alkyl substituents”, which may be selected from, but not limited to one or more of the following groups: —R′, —OR′, ⁇ O, ⁇ NR′, ⁇ N—OR′, —NR′R′′, —SR′, halogen, —SiR′R′′R′′′, OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, NR′ C(O)NR′′R′′′, —NR′′C(O) 2 R′, —NR′′′′′—C(NR′R
  • R′, R′′, R′′′, R′′′′ and R′′′′′ are each independently and preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., 1 to 3 halogens-substituted aryl), substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl.
  • each R is to be selected independently as each of these groups when more than one R′, R′′, R′′′, R′′′′, and R′′′′′ exist.
  • R′ and R′′ When R′ and R′′ are attached to the same nitrogen atom, they can form a 5-, 6- or 7-membered ring together with the nitrogen atom.
  • —NR′R′′ is meant to include, but not limited to 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include a group formed by the linkage of carbon atom with a non-hydrogen group, such as haloalkyl (e.g., —CF 3 , —CH 2 CF 3 ) and acyl (e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , etc.).
  • haloalkyl e.g., —CF 3 , —CH 2 CF 3
  • acyl e.g., —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OCH 3 , etc.
  • aryl and heteroaryl substituents are generally referred to as “aryl substituents”, and selected from, for example —R′, —OR′, —NR′R′′, —SR′, -halogen, —SiR′R′′R′′′, OC(O)R′, —C(O)R′, —CO2R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, NR′C(O)NR′′R′′′, —NR′′C(O)2R′, —NR′′′′—C(NR′R′′R′′′) ⁇ NR′′′′′, NR′′′′C(NR′R′′) ⁇ NR′′′′′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R′′, NR′′SO 2 R′, —CN, —NO 2 , —N 3 , —CH(
  • each R is to be selected independently as each of these groups when more than one R′, R′′, R′′′, R′′′′, and R′′′′′ exist.
  • Two substituents of the adjacent atoms on an aryl or heteroaryl ring may optionally be substituted by a substituent of the formula -T-C(O)—(CRR′)q-U—, wherein T and U are independently selected from —NR—, —O—, CRR′— or a single bond, and q is an integer of 0-3.
  • halogen or “halo” by itself or as part of another substituent refers to fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C1-C4)alkyl is intended to include, but not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.
  • haloalkyl examples include, but not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.
  • Alkoxy represents any alkyl defined above and having the specified number of carbon atoms attached by oxygen.
  • C 1-6 alkoxy means alkoxy including C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • alkoxy include, but not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and sec-pentoxy.
  • Cycloalkyl means a saturated ring, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • 3-7 cycloalkyl means cycloalkyl including C 3 , C 4 , C 5 , C 6 and C 7 .
  • Alkenyl means straight or branched hydrocarbon chain, wherein one or more carbon-carbon double bonds may be present in any stable site on the chain, such as vinyl and propenyl.
  • halo or “halogen” used herein refers to fluoro, chloro, bromo and iodo.
  • hetero used herein means a hetero atom or hetero radical (i.e., free radical containing a hetero atom), including all atoms except carbon (C) and hydrogen (H), and also including free radicals containing the above hetero atoms.
  • the related examples include oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), and optionally substituted —C( ⁇ O)N(H)—, —N(H)—, —C( ⁇ NH)—, —S( ⁇ O) 2 N(H)— or —S( ⁇ O)N(H)—.
  • ring used herein represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.
  • the so-called ring includes fused ring.
  • the number of ring atoms is usually defined as the member number of the ring, for example, “5-7 membered ring” means that 5 to 7 atoms are arranged surrounding the ring. Unless otherwise specified, the ring optionally contains 1 to 3 hetero atoms.
  • 5-7 membered ring includes for example, phenyl pyridine and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidyl, but excluding phenyl.
  • ring also includes a ring system containing at least one ring, wherein each ring independently meets the above definition.
  • heterocycle or “heterocyclo” used herein means a stable 5-, 6- or 7-membered mono-cycle, or bi-cycle or 7-, 8-, 9- or 10-membered bi-cycle heterocycle, which may be saturated, partially unsaturated or unsaturated (aromatic) and contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein the above any heterocycle may be fused to a benzene ring to form a bi-cycle. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p).
  • Nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents already defined herein).
  • the heterocycle may be attached to the pendant group of any heteroatom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycle described herein may have a substitution on a carbon or nitrogen position. Nitrogen atom in the heterocycle is optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle is more than 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle is not more than 1.
  • aromatic heterocyclic group refers to a stable 5-, 6- or 7-membered mono-cycle, or bi-cycle or aromatic ring of 7-, 8-, 9- or 10-membered bi-cycle heterocyclic group which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms in an aromatic heterocycle is not more than one.
  • Bridged ring is also included in the definition of heterocycle.
  • Bridged ring is formed when one or more atoms (ie, C, O, N or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged ring includes, but not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that one bridge always converts a monocycle to a tricycle. In a bridged ring, the substituents on the ring may also be present on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, ind
  • hydrocarbyl or lower-level terms thereof (such as alkyl, alkenyl, alkynyl, and phenyl, etc.), by itself or as part of another substituent, means a straight, branched chain or cyclic hydrocarbon radicals or any combinations thereof. They may be fully saturated, mono- or polyunsaturated, can be mono-, di- or poly-substituted, may be a monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methenyl), may also includes divalent or multivalent free radical and have a specified number of carbon atoms (for example, C 1 -C 10 indicates 1 to 10 carbon atoms).
  • hydrocarbyl includes, but is not limited to aliphatic hydrocarbyl and aromatic hydrocarbyl.
  • the aliphatic hydrocarbyl includes linear and cyclic hydrocarbyl, specifically includes but not limited to an alkyl, alkenyl, and alkynyl.
  • the aromatic hydrocarbyl includes but is not limited to 6-12 membered aromatic hydrocarbyl such as phenyl, and dimethyl fumarate.
  • alkyl means a straight or branched radical or a combination thereof which may be fully saturated, mono- or polyunsaturated, and may include a divalent or multivalent radical.
  • saturated hydrocarbyl radical examples include, but are not limited to, the group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, n-amyl, n-hexyl, n-heptyl, n-octyl and homologs or isomers thereof.
  • the unsaturated alkyl has one or more double or triple bonds.
  • unsaturated alkyl examples include but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.
  • heterohydrocarbyl or lower-level terms thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, etc.), by itself or as part of another substitutent, means a stable straight, branched chain or cyclic hydrocarbon radicals or any combinations thereof, which have a specified number of carbon atoms and at least one hetero atom.
  • heteroalkyl by itself or in combination with another term represents a stable straight chain, branched chain hydrocarbon radical or combinations thereof which have a specified number of carbon atoms and at least one hetero atom.
  • a hetero atom is selected from B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized.
  • Heteroatom B, O, N and S may be replaced at any interior position in a heterohydrocarbyl (including the position where the hydrocarbyl attaches to the rest part of the molecule).
  • Examples include, but are not limited to, —CH2-CH2-O—CH3, —CH2-CH2-NH—CH3, —CH2-CH2-N(CH3)-CH3, —CH2-S—CH2-CH3, —CH2-CH2, —S(O)—CH3, —CH2-CH2-S(O)2-CH3, —CH ⁇ CH—O—CH3, —CH2-CH ⁇ N—OCH3, and —CH ⁇ CH—N(CH3)-CH3.
  • Up to two consecutive heteroatoms can be present, such as, —CH 2 —NH—OCH 3 .
  • alkoxy alkylamino and “alkylthio” (or thioalkyl) are used by their conventional meanings and refer to those alkyl groups connected to the remainder of the molecule via an oxygen atom, an amino or a sulfur atom, respectively.
  • cyclohydrocarbyl “heterocyclohydrocarbyl” or lower-level terms thereof (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by itself or in combination with another term represents cyclized “hydrocarbyl” or “heterohydrocarbyl”.
  • heterohydrocarbyl or heterocyclohydrocarbyl e.g. heteroalkyl, and heterocycloalkyl
  • one heteroatom can occupy the position where the heterocycle attaches to the remainder position of the molecule.
  • cycloalkyl examples include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like.
  • heterocycloalkyl examples include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl means a polyunsaturated aromatic substituent which is a single ring or multiple rings (preferably 1-3 rings) wherein they are fused together or linked covalently.
  • heteroaryl refers to an aryl (or ring) containing one to four hetero atoms.
  • the exemplary hetero atom is usually B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized.
  • a heteroaryl may attach to the rest part of a molecule via a heteroatom.
  • Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl
  • the aryl when combined with other terms (e.g. aryloxy, arylthio, arylalkyl), the aryl includes all the aryl and heteroaryl ring as defined above.
  • the term “aralkyl” is meant to include free radicals formed from one aryl attached to one alkyl (e.g. benzyl, phenethyl, pyridylmethyl, and the like).
  • the carbon atom of an alkyl e.g., methylene
  • leaving group refers to a functional group or atom which can be substituted by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction).
  • a substitution reaction such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine and iodine; sulfonate groups, such as mesylate, tosylate, brosylate, tosylate and the like; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to “nitrogen protecting group”, “hydroxyl protecting group” or “sulphur protecting group.”
  • amino protecting group means a protecting group suitable for blocking side reactions on nitrogen of the amino.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g.
  • acetyl, trichloroacetyl or trifluoroacetyl alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis-(4′-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trity
  • hydroxy protecting group refers to a protecting group suitable for blocking side reactions on the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl such as methyl, ethyl and t-butyl; acyl, e.g. alkanoyl (e.g. acetyl); arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl such as trimethylsilyl (TMS) and tert-butyl dimethyl silyl (TBS) and the like.
  • alkyl such as methyl, ethyl and t-butyl
  • acyl e.g. alkanoyl (e.g. acetyl)
  • arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluor
  • LDA lithium diisopropylamide
  • TMPLi lithium 2,2,6,6-tetramethylpiperidide.
  • DCM represents dichloromethane
  • EtOAc represents ethyl acetate
  • EtOH represents ethanol
  • MeOH represents methanol
  • TFA trifluoroacetic acid
  • PCC represents pyridinium chlorochromate
  • NaCNBH 3 represents sodium cyanoborohydride
  • THF represents tetrahydrofuran
  • DCE 1,2-dichloroethane
  • FA represents formic acid
  • MeCN represents acetonitrile
  • Pd/C represents palladium on carbon
  • BF 3 -Et2O represents boron trifluoride-diethyl ether complex
  • TBAF represents tetra-butylammonium fluoride
  • TLC represents thin layer chromatography
  • HPLC represents high performance liquid chromatography
  • SFC represents supercritical fluid chromatography
  • FIG. 1 shows the results of the in vivo pharmacodynamic evaluation experiment of the compounds in a mice model infected with spray of M. tuberculosis . After the mice were infected for 35 days, all mice were euthanized, the lung tissue was taken out and ground, and the amount of bacteria load was calculated after spotting on a plate.
  • the compounds of the present invention can be synthesized by a variety of methods and through a series of synthetic steps well known to those skilled in the art.
  • compounds of formula (I) can be prepared from the intermediate of formula (II).
  • W represents a suitable leaving group, for example halogen (eg, bromine) which can react with aryl boric acid or aryl borate.
  • W may also represent an aryl borate which can react with an aryl halide.
  • the reaction requires a suitable catalyst (eg, Pd (dppf)Cl 2 ), a suitable base (e.g., K 2 CO 3 ), and a suitable solvent (eg, 1,4-dioxane/water).
  • a suitable catalyst eg, Pd (dppf)Cl 2
  • a suitable base e.g., K 2 CO 3
  • a suitable solvent eg, 1,4-dioxane/water
  • Dibromoheterocycle is reacted with benzaldehyde in step A of Reaction Scheme 2.
  • the reaction is carried out in a suitable base (such as n-butyl lithium), and a suitable solvent (eg, THF) at ⁇ 78° C. to ⁇ 50° C.
  • a suitable base such as n-butyl lithium
  • THF a suitable solvent
  • the adduct obtained from the above step is reacted with triethylsilane and boron trifluoride in DCM at a high temperature.
  • DIPA is reacted with n-butyl lithium in THF in step C at ⁇ 78° C. to ⁇ 50° C.
  • Bromide 11-a is reacted with bis(pinacolato)diboron in a suitable catalyst (such as Pd(dppf)Cl 2 ), a suitable base (such as potassium acetate) and a suitable solvent (such as 1,4-dioxane) in the next step D.
  • a suitable catalyst such as Pd(dppf)Cl 2
  • a suitable base such as potassium acetate
  • a suitable solvent such as 1,4-dioxane
  • reaction products can be isolated from the reaction medium and if desired, can be purified by using the purification methods well known to the skilled in the art, such as extraction, crystallization and chromatography. More obviously, for the reaction products having more than one enantiomers, the compound of formula (I) can be separated into isomers thereof by the separation methods well known by the skilled in the art, in particular, preparative chromatography, such as preparative HPLC, SFC and the like.
  • the compound of formula (I) can also be prepared from the intermediate of formula (II) and the intermediate of formula (IV) according to Reaction Scheme 3:
  • N-butyllithium was added to a suitable base (eg, diisopropylamine) and a suitable solvent (such as tetrahydrofuran). All variables have the same definitions as in formula (I).
  • the reaction rate can be elevated by stirring.
  • the reaction temperature is ⁇ 78° C. to ⁇ 50° C.
  • W of the raw material represents a suitable leaving group, for example halogen (eg, bromine) which can be reacted with aryl boric acid or aryl borate.
  • the reaction requires a suitable catalyst (eg, Pd(dppf)Cl 2 ), a suitable base (e.g., K 2 CO 3 ), and a suitable solvent (eg, 1,4-dioxane/water).
  • a suitable catalyst eg, Pd(dppf)Cl 2
  • a suitable base e.g., K 2 CO 3
  • a suitable solvent eg, 1,4-dioxane/water
  • the reaction is preferrably carried out at a high temperature.
  • the adduct is reacted with a benzaldehyde derivative.
  • the reaction requires a suitable base (e.g., TMPLi or LDA) and a suitable solvent (such as THF) and is carried out at ⁇ 78° C. to 20° C.
  • step C hydroxyl is reduced in silane (eg, triethylsilane).
  • silane eg, triethylsilane.
  • the reaction is carried out in TFA at a high temperature.
  • the intermediate of formula (IV) can be purchased from the market or prepared by the general reaction schemes well known to the skilled in the art.
  • the intermediate of formula (IV) can be prepared according to Reaction Scheme 5:
  • Reaction Scheme 5 comprises the reaction of acetyl derivative of R 3 (eg, cyclohexylethyl ketone), polymethanol, and a primary or secondary amine HNR 4 R 5 (preferably a salt form) in a suitable acid (e.g., hydrochloric acid) and an appropriate solvent (e.g., alcohols, such as ethanol).
  • a suitable acid e.g., hydrochloric acid
  • an appropriate solvent e.g., alcohols, such as ethanol
  • the compound of formula (I) can also be prepared from the intermediate of formula (III) as raw material according to Reaction Scheme 6:
  • the compounds which can not be prepared successfully according to Reaction Scheme 3 can be prepared according to Reaction Scheme 6. All variables have the same definitions as in formula (I).
  • the compound of formula Ill as raw material of step A in Reaction Scheme 6 is reacted with a benzaldehyde derivant.
  • the reaction is carried out in a suitable base (such as TMPLi or LDA), and a suitable solvent (eg, THF) at ⁇ 78° C. to 20° C.
  • a suitable solvent eg, THF
  • the alcohol is oxidized by an oxidant (e.g., PCC or Dess-Martin).
  • the reaction solvent is DCM and the like.
  • step C the carbonyl is subjected to an addition reaction in an organometallic reagent (e.g., allylmagnesium bromide) and an appropriate solvent (e.g., THF).
  • organometallic reagent e.g., allylmagnesium bromide
  • an appropriate solvent e.g., THF
  • step D the olefin is oxidized by an oxidant (e.g., OsO 4 /NalO 4 ) in a suitable solvent, which typically requires the addition of 2,6-lutidine.
  • the intermediate obtained from step D and the salt form of a primary or secondary amine (HNR 5 R 6 ) are reacted to introduce the amino (—NR 5 R 6 ) under a reductive amination condition.
  • the reaction is carried out in a suitable reducing agent (such as, NaBH 3 CN or NaBH(OAc) 3 ) and a suitable solvent (eg, dichloroethane, methanol or dich
  • the compound of formula (I) can also be formed from the compound per se by conversion of functional groups well known by the skilled in the art.
  • the compounds of the present invention may be prepared by a variety of synthetic methods well known to the skilled, including the following specific embodiments, the embodiments formed by the following specific embodiments in combination with other chemical synthesis methods and the equivalent replacement well known to the skilled in the art.
  • the preferred embodiments include, but are not limited to the examples of the present invention.
  • HPLC analysis was conducted using Shimadzu LC20AB system equipped with Shimadzu SIL-20A autosampler and Shimadzu DAD: SPD-M20A LC20AB detector through Xtimate C18 column (3 ⁇ m packing material, 2.1 ⁇ 300 mm).
  • 0-60AB_6 min method was carried out using linear gradient elution from 100% A (A is 0.0675% TFA in water) to 60% B (B is 0.0625% TFA solution in MeCN) over 4.2 minutes, and then 60% B was used to elute for 1 minute.
  • the column was re-equilibrated for 0.8 minutes to 100:0 and the total run time was 6 minutes.
  • 10-80AB 6 min method was carried out using linear gradient elution from 90% A (A is 0.0675% TFA in water) to 80% B (B is 0.0625% TFA solution in MeCN) over 4.2 minutes, and then 80% B was used to elute for 1 minute.
  • the column was re-equilibrated for 0.8 minutes to 90:10 and the total run time was 6 minutes.
  • the column temperature was 50° C., and the flow rate was 0.8 mL/min.
  • the scanning wavelength of diode array detector was 200-400 nm.
  • Thin layer chromatography was conducted on Sanpont-group silica gel GF254.
  • the spots were detected by irradiation of the commonly used ultraviolet light. In some cases, the spots were detected by other means.
  • iodine formed from thorough blend of 10 g of silica gel and about 1 g iodine
  • vanillin formed from dissolution of about 1 g vanillin in 100 mL of 10% H 2 SO 4
  • ninhydrin commercially available from Aldrich
  • a special color-developing agent formed from thorough blend of (NH 4 ) 6 .Mo 7 O 24 .4H 2 O, 5 g (NH 4 ) 2 Ce(IV) (NO 3 ) 6 , 450 mL of H 2 O and 50 mL of concentrated H 2 SO 4 ) was used to develop the TLC plate to detect the compound.
  • the flash column chromatography was conducted on 40-63 ⁇ m (230-400 mesh) silica gel from Silicycle using a method similar to the technique disclosed in Still, W. C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923-2925.
  • the typical solvent used in flash column chromatography or thin-layer chromatography was a mixture of dichloromethane/methanol, ethyl acetate/methanol, and hexane/ethyl acetate.
  • the preparative chromatography analysis was conducted by Gilson-281 Prep LC 322 system using Gilson UV/VIS-156 detector.
  • the chromatographic column used was Agella Venusil ASB Prep C18, 5 ⁇ m, 150 ⁇ 21.2 mm; Phenomenex Gemini C18, 5 m, 150 ⁇ 30 mm; Boston Symmetrix C18, 5 L m, 150 ⁇ 30 mm; or Phenomenex Synergi C18, 4 ⁇ m, 150 ⁇ 30 mm.
  • the flow rate was 25 mL/min and a low gradient of acetonitrile/water was used to elute the compound, wherein 0.05% HCl, 0.25% HCOOH or 0.5% NH 3 .H 2 O was contained in the water.
  • the total run time was 8-15 minutes.
  • the chromatographic conditions for AS-H_3_40_2.35 ML Chiralpak AS-H column (250 ⁇ 4.6 mm I.D., 5 um packing material), 40% methanol (0.05% DEA)—CO 2 as a mobile phase; 2.35 mL/min of flow rate; 220 nm of detection wavelength.
  • the chromatographic conditions for OD-H_3_40_2.35M Chiralcel OD-H column (250 ⁇ 4.6 mm I.D, 5 um packing material), 40% methanol (0.05% DEA)—CO 2 as a mobile phase; 2.35 mL/min of flow rate; 220 nm of detection wavelength.
  • the preparative SFC analysis was conducted using Waters Thar 80 Pre-SFC system equipped with Gilson UV detector.
  • the chromatographic column used was Chiralcel OD-H (250 ⁇ 4.6 mm I.D, 5 ⁇ m packing material) or Chiralpak AD-H (250 ⁇ 4.6 mm I.D, 5 ⁇ m packing material).
  • the flow rate was about 40-80 mL/min, the low gradient of ethanol-carbon dioxide or methanol-carbon dioxide was used to elute the compound, wherein methanol or ethanol contained 0.05% NH 3 .H 2 O, 0.05% DEA or 0.1% MEA and the total run time was 20-30 minutes.
  • the present invention provides novel compounds, primarily pyridine derivatives. Such compounds can inhibit the growth of mycobacteria so that they can be used to treat the related diseases caused by mycobacteria, especially by M. tuberculosis, M. bovis, M. avium and M. marinum.
  • a and “B” are a mixture of isomers (especially enantiomers), they can be further separated.
  • the portion firstly isolated is referred to as “A1” and “B1”, and the second portion separated is referred to as “A2” and “B2”.
  • the “A1”, “A2” and “B1”, “B2” (enantiomeric) isomers can be clearly distinguished by a person skilled in the art using some methods such as X-ray diffraction.
  • the diastereoisomer (A or B), or enantiomer (A1, A2, B1, B2) of the new product is from the corresponding part of the former product.
  • 3,5-dibromo-2-methoxypyridine (118 g, 443 mmol) was dissolved in 1.2 L of anhydrous ethyl ether, n-butyllithium (2.5M n-hexane solution, 195 mL, 487 mmol) was added slowly at ⁇ 78° C. and stirred for 0.5 hours at ⁇ 78° C.
  • Benzaldehyde (47.0 g, 443 mmol) was dissolved in 100 mL of anhydrous ethyl ether and was added slowly to the reaction system at ⁇ 78° C. The mixture was slowly warmed to 15-25° C. and stirred for 1 hour.
  • Step 3 1-(5-bromo-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one (58.8 g, 259 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran and added slowly to the reaction system at ⁇ 70° C. Then the reaction mixture was stirred for another 1-2 hours. The reaction was quenched using 600 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 200 mL ethyl acetate each time for three times.
  • Step 4 4-(dimethylamino)-1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • intermediate B (2.00 g, 3.62 mmol), 1,2-dibromobenzene (1.02 g, 4.34 mmol), potassium acetate (710 mg, 7.24 mmol) and tetrakis(triphenylphosphine)palladium (209 mg, 0.18 mmol) were added to a mixed solution of dioxane/water.
  • the temperature was raised to 80° C. and stirred at this temperature under nitrogen for 16 hours. Completion of the reaction was monitored by LCMS.
  • the reaction mixture was added to water (40 mL) and extracted with ethyl acetate (30 mL ⁇ 3).
  • the product was prepared by the reaction of intermediate A and cyclopropyl boronic acid.
  • the crude product was purified by preparative HPLC (GX-D; Agella Venusil ASB C18 150*21.2 mm*5 um; acetonitrile 70%-100%; water (0.225% HCl); 25 mL/min) to give component A and component B.
  • the product was prepared by the reaction of intermediate A and 4-pyridine boronic acid.
  • the crude product was purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 15%-45%; H 2 O (+0.225% HCOOH); 25 mL/min) to give component A and component B.
  • the product was prepared by the reaction of intermediate A and 4-pyridine boronic acid.
  • the crude product was purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 30%-54%; H 2 O (+0.25% HCl); 25 mL/min) to give component A and component B.
  • Step 1 tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2, 5-dihydro-1H-pyrrol-1-carbonate
  • Step 2 tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrol-1-carbonate
  • tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrol-1-carbonate 600 mg, 1.9 mmol
  • pinacol borate 480 mg, 1.9 mmol
  • Pd(dppf)Cl 2 140 mg, 0.19 mmol
  • diphenylphosphino ferrocene 100 mg, 0.19 mmol
  • potassium acetate 550 mg, 0.57 mmol
  • Step 3 tert-butyl 3-(5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxypyridin-3-yl)-2, 5-dihydro-1H-pyrrol-1-carbonate
  • Step 4 tert-butyl 3-(5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxypyridin-3-yl)pyrrol-1-carbonate
  • Step 5 4-(dimethylamino)-1-(2-methoxy-5-(pyrrolidin-3-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was then concentrated and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 10%-40%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • Component B was separated by chiral SFC (Berger MultiGramTM SFC, Mettler Toledo Co, Ltd; IC 250 mm*20 mm, 10 um; supercritical CO 2 /MeOH (0.05% aqueous ammonia)—50/50; 70 ml/min; 220 nm) to give compound 59 (B1) (26.9 mg, 6.46% yield) and compound (B2) (19.47 mg, 4.68% yield) as white solid.
  • Compound 57 (A1)/compound 58 (A2) 1 H NMR (400 MHz, METHANOL-d 4 ): ⁇ 8.66 (br. s., 1H), 8.50 (s, 2H), 8.33 (br.
  • Step 1 1-(5-(cyclopentyl-1-en-1-yl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 2 1-(5-cyclopentyl-2-methoxypyridin-3-yl)-4-(dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was filtered and the filtrate was dried by rotary evaporation and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 34%-64%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 34%-64%; water (0.225% formic acid); 25 mL/min
  • Step 1 1-(5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 2 4-(dimethylamino)-1-(2-methoxy-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was filtered and the filtrate was dried by rotary evaporation and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 27%-57%; H 2 O (+0.0023 FA); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 27%-57%; H 2 O (+0.0023 FA); 25 mL/min
  • Component B was separated by chiral SFC (Berger MultiGramTM SFC, Mettler Toledo Co, Ltd; IC-10 um; supercritical CO 2 /MeOH (0.05% aqueous ammonia)—60/40; 70 ml/min; 220 nm) to give compound 77 (B1) (12.08 mg, 6.9% yield) and compound 78 (B2) (12.75 mg, 7.3% yield) as white solid.
  • Step 1 tert-butyl 5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxy-5′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-carboxylate
  • Step 2 4-(dimethylamino)-1-(6-methoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-5-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 3 4-(dimethylamino)-1-(2-methoxy-5-(piperidin-4-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was filtered and the filtrate was concentrated to give crude product (0.5 g) which was purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 15%-50%; H 2 O (+0.0023 FA); 25 ml/min) to give compound 79 (A) (57.27 mg, 23.4% yield) and compound 80 (B) (77.82 mg, 26.9% yield) as a white solid.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 15%-50%; H 2 O (+0.0023 FA); 25 ml/min
  • reaction liquid was filtered and the filtrate was concentrated and separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 25%-55%; H 2 O (+0.0023 FA); 25 mL/min) to give compound 81 (A) (222.21 mg, 43.2% yield) and compound 82 (B) (124.27 mg, 29.5% yield) as white solid.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; MeCN: 25%-55%; H 2 O (+0.0023 FA); 25 mL/min
  • intermediate A and (2-fluorophenyl) boronic acid were used to prepare the crude product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • intermediate A and (4-fluorophenyl) boronic acid were used to prepare.
  • the crude product was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 25%-55%; water (0.225% FA); 25 mL/min) to give component A and component B.
  • the product was prepared by intermediate A and (4-fluorophenyl) boronic acid.
  • the crude product was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 25%-55%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • intermediate B was reacted with 2-bromopyridine to prepare the crude product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • Compound 95(A1)/compound 96 (A2) 1 H NMR (400 MHz, METHANOL-d 4 ): ⁇ 9.03 (br. s., 1H), 8.76-8.61 (m, 3H), 8.55 (br.
  • Step 1 4-(dimethylamino)-1-(2-methoxy-5-vinylpyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 2 5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxynicotinaldehyde
  • Step 3 4-(dimethylamino)-1-(5-((dimethylamino)methyl)-2-methoxypyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction mixture was concentrated under reduced pressure, and separated by preparative HPLC (GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 10%-40%; water (0.225% formic acid); 25 mL/min) to give compound 99 (A) (60.33 mg, 14.1% yield) and compound 100 (B) (105.82 mg, 24.7% yield) as white solid.
  • Step 1 4-(dimethylamino)-1-5-(2-ethoxyvinyl-2-methoxypyridin-3-yl)-2-(naphthalen-1-yl)-phenylbutan-2-ol
  • Step 2 2-(5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxypyridin-3-yl)acetaldehyde
  • Step 3 4-(dimethylamino)-1-(5-(2-(dimethylamino)ethyl)-2-methoxypyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 1 1-(5-(cyclohex-1-en-1-yl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 2 1-(5-cyclohexyl-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • the filtrate was dried by rotary evaporation, and separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 34%-64%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • intermediate A was reacted with (2-chlorophenyl)boronic acid to prepare the crude product which was separated and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 26%-56%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 26%-56%; water (0.225% formic acid); 25 mL/min
  • Compound 115 (A1)/compound 116 (A2) 1 H NMR (400 MHz, METHANOL-d 4 ): ⁇ 8.69 (br. s., 2H), 8.53 (br.
  • intermediate B and 1,3-dibromobenzene were used to prepare crude product which was separated and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • intermediate B and 1,4-dibromobenzene were used to prepare crude product which was separated and purified by preparative HPLC (HPLC-A; SYNERGI; acetonitrile 25%-50%; water (0.225% formic acid); 80 mL/imin) to give component A and component B.
  • intermediate A and 4-cyanophenylboronic acid were used to prepare crude product which was separated and purified by preparative HPLC (GX-B; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 31%-61%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • intermediate B and 4-bromoisothiazole were used to prepare crude product which was separated and purified by preparative HPLC (GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 25%-55%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • Component B was separated by chiral SFC (Berger MultiGramTM SFC, Mettler Toledo Co, Ltd, IC-10 um; supercritical CO 2 /MeOH (0.05% aqueous ammonia)—60/40; 70 ml/min; 220 nm) to give compound 169 (B1) (34.56 mg, 1.91% yield) and compound 170 (B2) (32.81 mg, 1.81% yield) as white solid.
  • Step 1 4-(dimethylamino)-1-(2-methoxy-5-(prop-1-en-2-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • Step 2 4-(dimethylamino)-1-(5-isopropyl-2-methoxypyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was concentrated and then adjusted with ammonium chloride solution to pH 9.20 mL of water was added and then the mixture was extracted with dichloromethane/methanol (10/1, 50 mL ⁇ 3). The combined organic phase was washed with 50 mL of saturated brine twice, dried over anhydrous sodium sulfat and concentrated to give 4-(dimethylamino)-1-(5-isopropyl-2-methoxypyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (200 mg, 25%).
  • Step 2 1-(5-(5-chlorothiophen-3-yl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • intermediate B was reacted with 3-bromo-2-chlorothiophene to produce crude product which was separated and purified by preparative HPLC (HPLC-D; SYNERGI-C 200*50 10 um; acetonitrile 25%-50%; water (0.225% formic acid); 80 mL/min) to give component A and component B.
  • component B was produced by the reaction of 1-(5-(3,6-dihydro-2H-thiopyran-4-yl)-2-methoxy-3-pyridyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-butan-2-ol (the mixture of compound 257 and compound 258).
  • Step 1 (5-(4-(dimethylamino)-2-hydroxyl-2-(naphthalen-1-yl)-1-phenylbutyl)-6-methoxypyridin-3-yl)boronic acid
  • Step 2 4-(dimethylamino)-1-(2-methoxy-5-(pyrrolidin-1-yl)pyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • reaction liquid was filtered and the filtrate was concentrated to give crude product which was separated and purified by preparative HPLC (GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give compound 261 (A) (2.7 mg, 1.3% yield) and compound 262 (B) (2.8 mg, 1.3% yield) as white solid.
  • Step 2 4-(dimethylamino)-1-(2-methoxy-5-prop-1-ynyl-3-pyridyl)-2-(1-naphthyl)-1-phenylbutan-2-ol
  • intermediate A (1.20 g, 2.37 mmol) and tributyl (prop-1-ynyl)stannane (3.5 g, crude product) were dissolved in 40 mL of N,N-dimethyl formamide and a catalytic amount of Pd(dppf)Cl 2 (200 mg, cat.) was added to the mixed liquid in one portion at 15-35° C.
  • the reaction mixture was stirred at 80° C. for 10 minutes. LCMS showed the reaction was complete.
  • the reaction mixture was cooled to 15-35° C. and the reaction was quenched with 100 mL of saturated potassium fluoride solution and stirred for 20 minutes.
  • aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3) and the combined organic phase was washed with saturated brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate and then filtered.
  • intermediate A and 2-(4-chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were used to prepare crude product which was separated by preparative HPLC (GX-G; Phenomenex Synergi C18 150 ⁇ 30 mm ⁇ 4 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • Component B was separated by chiral SFC (Column AD-10 um; supercritical CO 2 /EtOH (0.2% aqueous ammonia)—75/25; 60 mL/min; 220 nm) to give compound 305 (B1) (56.3 mg, 5.13% yield) and compound 306 (B2) (73.17 mg, 6.66% yield).
  • Step 2 4-(dimethylamino)-1-[2-methoxy-5-(2-phenylethynyl)-3-pyridyl]-2-(1-naphthyl)-1-phenyl-butan-2-ol
  • intermediate A and 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxyborate were used to prepare crude product which was separated by preparative HPLC (GX-G; Phenomenex Synergi C18 150 ⁇ 30 mm ⁇ 4 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • 2,6-dichloronicotinic acid (15.0 g, 0.0785 mol) was dissolved in 60 mL of ethanol, 20 mL of dimethyl ether and 10 mL of water.
  • Potassium carbonate (32.0 g, 0.2355 mol)
  • phenylboronic acid (11.5 g, 0.0942 mol)
  • Pd(PPh 3 )Cl 2 (2.75 g, 0.003925 mmol) were added and heated to 100° C. and stirred for 5 h.
  • the reaction liquid was poured into 30 mL of water and extracted with ethyl acetate (50 mL ⁇ 3).
  • N,2-dimethoxy-N-methyl-6-phenylnicotinamide (500 mg, 1.83 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran and lithium aluminum tetrahydride (140 mg, 3.66 mmol) was added and warmed to 25° C. and stirred for 2 h.
  • the reaction liquid was quenched with 10 mL of 10% aqueous sodium hydroxide solution.
  • the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 5 (Z)—N′-((2-methoxy-6-phenylpyridin-3-yl)methylene)-4-methyl benzene sulfonyl hydrazide
  • Step 7 4-(dimethylamino)-1-(2-methoxy-6-phenylpyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • 3-(dimethylamino)-1-phenylpropan-1-one (1.62 g, 9.12 mmol) was dissolved in 10 mL of tetrahydrofuran and then slowly added dropwise to the reaction liquid. Then the mixture was stirred at ⁇ 70° C. for another 2 h. The reaction was quenched with saturated ammonium chloride solution (20 mL).
  • Benzaldehyde (13.7 g, 130 mmol) was dissolved in anhydrous tetrahydrofuran(100 mL) and then slowly added dropwise to the reaction liquid and stirred at room temperature for another 12 h. The reaction was quenched with aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (300 mL ⁇ 3).
  • Step 4 4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-1,2-diphenylbutan-2-ol
  • 3-(dimethylamino)-1-benzenepropan-1-one (2.1 g, 7.6 mmol) was dissolved in 10 mL of tetrahydrofuran and then added slowly dropwise to the reaction liquid. Then the mixture was stirred at ⁇ 70° C. for another 2 h. At ⁇ 70° C., the reaction was quenched with saturated ammonium chloride solution (20 mL) and the reaction mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Compound 21 (A1)/compound 22 (A2): 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.67 (d, J 2.51 Hz, 1H), 8.54 (br.
  • 1-(2-fluorophenyl)ethanone (3.0 g, 21.7 mmol), dimethylamine hydrochloride (2.5 g, 30 mmol), paraformaldehyde (1.0 g, 32.6 mmol) and concentrated hydrochloric acid (0.1 mL) were dissolved in 20 mL of ethanol, heated to 80° C. to reflux and stirred for 12 h. The mixture was concentrated under reduced pressure, acidified with 3M hydrochloric acid, and washed with dichloromethane (15 mL ⁇ 3). The aqueous phase was basified with saturated aqueous sodium carbonate solution and pH was adjusted to 10. Then the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 2 4-(dimethylamino)-2-(2-fluorophenyl)-1-(2-methoxy-5-phenylpyridin-3-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-methoxy-5-phenylpyridine and 3-(dimethylamino)-1-(2-fluorophenyl)propan-1-one were used to prepare crude product which was separated by preparative HPLC (GX-D; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 26%-50%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 26%-50%; water (0.225% formic acid); 25 mL/min
  • 1-(2,3-difluorophenyl)ethanone (3.0 g, 19.2 mmol), dimethylamine hydrochloride (2.2 g, 27.0 mmol), paraformaldehyde (860 mg, 28.8 mmol) and concentrated hydrochloric acid (0.1 mL) were dissolved in 20 mL of ethanol, heated to 80° C. to reflux and stirred for 12 h. The mixture was concentrated under reduced pressure, acidified with 3M hydrochloric acid and washed with dichloromethane (15 mL ⁇ 3). The aqueous phase was basified with saturated aqueous sodium carbonate solution and pH was adjusted to 10. Then the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 2 2-(2,3-difluorophenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-methoxy-5-phenylpyridine was reacted with 1-(2,3-difluorophenyl)-3-(dimethylamino)propan-1-one to prepare the product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 25%-55%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 25%-55%; water (0.225% formic acid); 25 mL/min
  • 1-(3,5-difluorophenyl)ethanone (5.0 g, 32 mmol), dimethylamine hydrochloride (10.5 g, 128 mmol), paraformaldehyde (3.7 g, 123 mmol) and concentrated hydrochloric acid (0.1 mL) were dissolved in 30 mL of ethanol, heated to 80° C. to reflux and stirred for 12 h. The mixture was concentrated under reduced pressure, acidified with 3M hydrochloric acid and washed with dichloromethane (30 mL ⁇ 3). The aqueous phase was basified with saturated aqueous sodium carbonate solution and pH was adjusted to 10. Then the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 2 2-(3,5-difluorophenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-methoxy-5-phenylpyridine was reacted with 1-(3,5-difluorophenyl)-3-(dimethylamino)propan-1-one to prepare the product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 35%-59%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 35%-59%; water (0.225% formic acid); 25 mL/min
  • Compound 33 (A1)/compound 34 (A2): 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.63 (d, J 2.38 Hz, 1H), 8.54 (br.
  • 1-(2,5-difluorophenyl)ethanone (3.0 g, 19.2 mmol), dimethylamine hydrochloride (2.2 g, 27.0 mmol), paraformaldehyde (860 mg, 28.8 mmol) and concentrated hydrochloric acid (0.1 mL) were dissolved in 20 mL of ethanol, heated to 80° C. to reflux and stirred for 12 h. The mixture was concentrated under reduced pressure, acidified with 3M hydrochloric acid and washed with dichloromethane (20 mL ⁇ 3). The aqueous phase was basified with saturated aqueous sodium carbonate solution and pH was adjusted to 10. Then the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 2 2-(2,5-difluorophenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-methoxy-5-phenylpyridine was reacted with 1-(2,5-difluorophenyl)-3-(dimethylamino)propan-1-one to prepare the product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min
  • Compound 37 (A1)/compound 38 (A2): 1 H NMR (400 MHz, METHANOL-d 4 ) ⁇ 8.53 (d, J 2.38 Hz, 1H), 8.50 (br.
  • Step 1 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one
  • 1-(naphthalen-1-yl)ethanone 100 g, 0.587 mol
  • dimethylamine hydrochloride 49.2 g, 0.61 mol
  • paraformaldehyde 860 mg, 28.8 mmol
  • concentrated hydrochloric acid (0.75 mL) were mixed in 375 mL of ethanol and stirred at 80° C. under reflux for 12 hours.
  • the mixture was concentrated under reduced pressure and the residue was acidified with 3M HCl solution, and washed with dichloromethane (300 mL ⁇ 3).
  • the aqueous phase was basified with saturated sodium bicarbonate and extracted with ethyl acetate (200 mL ⁇ 3).
  • Step 2 4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-methoxy-5-phenylpyridine was reacted with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one to prepare the product which was separated by preparative HPLC (GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 27%-57%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 27%-57%; water (0.225% formic acid); 25 mL/min
  • Step 4 4-(dimethylamino)-1-(2-ethoxy-5-phenylpyridin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  • step 4 in Example 53 3-benzyl-2-ethoxy-5-phenylpyridine was reacted with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one to prepare the product which was separated by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 35%-65%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 35%-65%; water (0.225% formic acid); 25 mL/min
  • Component B was separated by chiral SFC (Chiralpak AD 250 ⁇ 30 mm I.D., 5 um; supercritical CO 2 /EtOH (0.2% NH 3 .H 2 O)—70/30; 60 ml/min; 220 nm) to give compound 219 (B1) (32.3 mg, 0.5% yield) and compound 220 (B2) (32.3 mg, 0.5% yield) as white solid.
  • the product was prepared from 2-methoxy-5-phenylpyridine and 4-chlorobenzaldehyde. Yield: 52.3%.
  • Step 3 1-(4-chlorophenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • the product was prepared from 3-(4-chlorobenzyl)-2-methoxy-5-phenylpyridine and 3-(dimethylamino)-1-phenylpropan-1-one, then separated and purified by preparative HPLC (GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 30%-60%; water (0.225% formic acid); 25 mL/min
  • the product was prepared from 2-methoxy-5-phenylpyridine and 3-chlorobenzaldehyde. Yield: 64%, LCMS (ESI) m/z: 326 (M+1).
  • the product was prepared from (3-chlorophenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 57%.
  • 1 H NMR 400 MHz, CHLOROFORM-d
  • LCMS m/z: 294 (M+1).
  • Step 3 1-(3-chlorophenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • the product was prepared from 2-methoxy-5-phenylpyridine and 2-fluorobenzaldehyde. Yield: 56%.
  • the product was prepared from (2-fluorophenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 59%.
  • Step 3 4-(dimethylamino)-1-(2-fluorophenyl)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • the product was prepared from 2-methoxy-5-phenylpyridine and 3-fluorobenzaldehyde. Yield: 66%, LCMS (ESI) m/z: 310 (M+1).
  • the product was prepared from (3-fluorophenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 53%, LCMS (ESI) m/z: 294 (M+1).
  • Step 3 4-(dimethylamino)-1-(3-fluorophenyl)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • the product was prepared from 2-methoxy-5-phenylpyridine and 4-fluorobenzaldehyde. Yield: 69%, LCMS (ESI) m/z: 310 (M+1).
  • the product was prepared from (4-fluorophenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 80%.
  • Step 3 4-(dimethylamino)-1-(4-fluorophenyl)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • the product was prepared from 2-methoxy-5-phenylpyridine and 2,3-dimethoxybenzaldehyde. Yield: 55.9%.
  • the product was prepared from (2,3-dimethoxyphenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 41.9%.
  • Step 3 1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • step 4 in Example 53 3-(2,3-dimethoxybenzyl)-2-methoxy-5-phenylpyridine and 3-(dimethylamino)-1-phenylpropan-1-one were used to prepare crude product which was separated by preparative HPLC (GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 23%-53%; water (0.225% formic acid); 25 mL/min) to give component A and component B.
  • preparative HPLC GX-G; Phenomenex Synergi C18 150*30 mm*4 um; acetonitrile 23%-53%; water (0.225% formic acid); 25 mL/min
  • 1-(3-chlorophenyl)ethanone (10.0 g, 64.7 mmol), dimethylamine hydrochloride (26.37 g, 323 mmol), paraformaldehyde (7.77 g, 258 mmol) and concentrated hydrochloric acid (1 mL) were mixed in 20 mL of ethanol and stirred at 80° C. to reflux for 16 h. The mixture was concentrated under reduced pressure and acidified with 3M hydrochloric acid solution and then washed with dichloromethane (50 mL ⁇ 3). The aqueous phase was basified with saturated sodium carbonate solution (50 mL ⁇ 3) and then extracted with ethyl acetate (50 ml ⁇ 3).
  • Step 2 2-(3-chlorophenyl)-1-(2, 3-dimethoxyphenyl)-4-(dimethylamino-1-(2-methoxy-5-phenylpyridin-3-yl)butan-2-ol
  • 1-(3,5-dichlorophenyl)ethanone (10.0 g, 52.90 mmol) and N-methylmethylamine hydrochloride (8.63 g, 105.80 mmol) were mixed in 100 mL of ethanol and paraformaldehyde (3.18 g, 35.30 mmol) and concentrated hydrochloric acid (2 mL) were added at 25° C. The mixture was stirred at 78° C. for 72 h and concentrated under reduced pressure. The mixture was poured into 80 mL of water, and washed with dichloromethane (50 mL ⁇ 2).
  • aqueous phase was basified with aqueous potassium carbonate solution, adjusted to pH 10, and then extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined ethyl acetate phase was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure to give 1-(3,5-dichlorophenyl)-3-(dimethylamino)propan-1-one (6.85 g, 52.6% yield) as a yellow oil which was used directly in the next step without further purification.
  • Step 2 2-(3,5-dichlorophenyl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-1-(2-methoxy-5-phenylpyridin-3-yl)butan-2-ol
  • the product was prepared from 2-methoxy-5-phenylpyridine and 2-fluoro-3-methoxybenzaldehyde. Yield: 38.2%.
  • the product was prepared from (2-fluoro-3-methoxyphenyl) (2-methoxy-5-phenylpyridin-3-yl)methanol. Yield: 60.2%.
  • Step 3 4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-1-(2-methoxy-5-phenylpyridin-3-yl)-2-phenylbutan-2-ol
  • preparative HPLC GX-D; Boston Symmetrix C18 ODS-R 150*30 mm*5 um; acetonitrile 25%-55%; water (0.225% formic acid); 25 mL/min
  • the product was prepared from 2-methoxy-5-phenylpyridine and 2-pyridine carboxaldehyde. Yield: 41%.
  • Step 2 O-((2-methoxy-5-phenylpyridin-3-yl) (pyridin-2-yl)methyl)thio-methyl dithiocarbonate
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10981891B2 (en) 2016-03-07 2021-04-20 The Global Alliance For Tb Drug Development, Inc. Antibacterial compounds and uses thereof

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WO2017121323A1 (zh) * 2016-01-13 2017-07-20 辰欣药业股份有限公司 一种吡啶衍生物类化合物的制备方法及其中间体和晶型
JP7184915B2 (ja) * 2018-02-28 2022-12-06 クレストーン・インコーポレーテッド 新規の抗マイコバクテリア複素環式アミド
IL277071B1 (en) 2018-03-08 2024-03-01 Incyte Corp Aminopyrizine diol compounds as PI3K–y inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
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CN110804016B (zh) * 2019-12-05 2022-11-04 福建省微生物研究所 抗结核分枝杆菌的二芳基喹啉衍生物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671667A (zh) 2002-07-25 2005-09-21 詹森药业有限公司 喹啉衍生物及其作为分枝杆菌抑制剂的应用
CN1976704A (zh) 2004-05-28 2007-06-06 詹森药业有限公司 取代的喹啉衍生物在治疗耐药性分枝杆菌性疾病中的用途
CN101232884A (zh) 2005-06-08 2008-07-30 詹森药业有限公司 作为抗菌剂的喹啉衍生物
CN101547907A (zh) 2006-12-06 2009-09-30 詹森药业有限公司 抗菌的喹啉衍生物
CN101553470A (zh) 2006-12-06 2009-10-07 詹森药业有限公司 抗菌的喹啉衍生物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103905A (en) * 1997-06-19 2000-08-15 Sepracor, Inc. Quinoline-indole antimicrobial agents, uses and compositions related thereto
RU2141322C1 (ru) * 1997-08-12 1999-11-20 Голощапов Николай Михайлович Иммуномодулятор с антимикобактериальной активностью "изофон", способ его получения и применения
ES2201674T3 (es) * 1998-01-26 2004-03-16 Smithkline Beecham Plc Derivados de quinolina con propiedades antibacterianas.
EP2552893B1 (en) * 2010-03-31 2014-10-29 Actelion Pharmaceuticals Ltd. Antibacterial isoquinolin-3-ylurea derivatives

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671667A (zh) 2002-07-25 2005-09-21 詹森药业有限公司 喹啉衍生物及其作为分枝杆菌抑制剂的应用
US7498343B2 (en) 2002-07-25 2009-03-03 Janssen Pharmaceutica N.V. Mycobacterial inhibitors
CN1976704A (zh) 2004-05-28 2007-06-06 詹森药业有限公司 取代的喹啉衍生物在治疗耐药性分枝杆菌性疾病中的用途
US20070249667A1 (en) 2004-05-28 2007-10-25 Janssen Pharmaceutica N.V. Use of Substituted Quinoline Derivatives for the Treatment of Drug Resistant Mycobacterial Diseases
CN101232884A (zh) 2005-06-08 2008-07-30 詹森药业有限公司 作为抗菌剂的喹啉衍生物
US7709498B2 (en) 2005-06-08 2010-05-04 Janssen Pharmaceutica N.V. Quinoline derivatives as antibacterial agents
CN101547907A (zh) 2006-12-06 2009-09-30 詹森药业有限公司 抗菌的喹啉衍生物
CN101553470A (zh) 2006-12-06 2009-10-07 詹森药业有限公司 抗菌的喹啉衍生物
US20100069366A1 (en) 2006-12-06 2010-03-18 Janssen-Cilag Antibacterial quinoline derivatives
US8415475B2 (en) 2006-12-06 2013-04-09 Janssen Pharmaceutica N.V. Antibacterial quinoline derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
International Search Report dated Oct. 22, 2015corresponding to International Patent Application No. PCT/CN2015/083626, filed on Jul. 9, 2015; 8 pages.
Mamolo et al, II Farmaco (1996), 51(1), pp. 65-71. *
Wu et al., Toxicology (2007), 236, pp. 1-6. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10981891B2 (en) 2016-03-07 2021-04-20 The Global Alliance For Tb Drug Development, Inc. Antibacterial compounds and uses thereof

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